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United States Patent |
6,060,320
|
Dorenkott
,   et al.
|
May 9, 2000
|
Method of verifying aspirated volume in automatic diagnostic system
Abstract
A nethod of verifying sample volume quantifies the fluid volume aspirated
and verifies sample uniformity by detecting the presence of foam or clots
in the sample. After aspiration, a pressure sensor is used to measure the
vacuum needed to hold up the column of fluid in the probe tip. By knowing
the geometry of the probe tip, the vacuum can be converted to a sample
weight and volume, based on sample densities. Non-ideal conditions, such
as foam on the surface of the fluid or a clot in the fluid, result in a
sample volume much lighter in the case if foam, or much greater, in the
case of a clot, than anticipated. The method also determines the elapsed
time of the aspiration. Foamy samples result in aspiration times shorter
than normal. Clotted samples result in aspiration times longer than
normal.
Inventors:
|
Dorenkott; Jeffrey S. (Olmsted, OH);
Panek; Carl F. (Olmsted, OH)
|
Assignee:
|
Bayer Corporation (East Walpole, MA)
|
Appl. No.:
|
985878 |
Filed:
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December 5, 1997 |
Current U.S. Class: |
436/54; 73/864.01; 73/864.15; 422/67; 422/81; 422/100; 436/50; 436/180 |
Intern'l Class: |
G01N 035/10 |
Field of Search: |
436/43,54,174,50,180
422/67,81,100,105,108,112
73/864,864.01,864.15
|
References Cited
U.S. Patent Documents
5013529 | May., 1991 | Itoh | 422/100.
|
5452619 | Sep., 1995 | Kawanabe et al. | 73/864.
|
5463895 | Nov., 1995 | Brentz | 73/61.
|
5488854 | Feb., 1996 | Kawanabe et al. | 73/19.
|
5488874 | Feb., 1996 | Kawanabe et al. | 73/863.
|
5537880 | Jul., 1996 | Takeda et al. | 73/864.
|
5540081 | Jul., 1996 | Takeda et al. | 73/37.
|
5723795 | Mar., 1998 | Merriam | 73/863.
|
Foreign Patent Documents |
0215534 | Mar., 1987 | EP.
| |
0341438 | Nov., 1989 | EP.
| |
0658769 | Jun., 1995 | EP.
| |
0753750 | Jan., 1997 | EP.
| |
0810438 | Dec., 1997 | EP.
| |
Other References
Omar S. Khalil et al., "Abbott Prism: A Multichannel Heterogeneous
Chemiluminescence Immunoassay Analyzer" Clin. Chem. 37/9, pp. 1540-1547
(1991).
|
Primary Examiner: Le; Long V.
Attorney, Agent or Firm: Gagnebin, III; Charles L., Moriarty; Gordon
Claims
We claim:
1. A method for verifying an aspirated volume of fluid, comprising:
placing a sample probe within a container of a sample fluid, the sample
probe having a predetermined geometry and the sample fluid having a
predetermined assumed density;
drawing a vacuum within the sample probe to cause fluid to be drawn into
the sample probe to aspirate the fluid;
measuring the pressure within the sample probe during aspiration of the
fluid to obtain a pressure profile;
determining a time of an initial rise in vacuum of the pressure profile;
determining a time of an initial decay in vacuum of the pressure profile;
determining a pressure at a predetermined point before the time of the
initial rise;
determining a pressure at a predetermined point after the time of the
initial decay;
calculating a pressure differential between the pressure before the initial
rise and the pressure after the initial decay; and
calculating a volume of fluid within the sample probe from the pressure
differential, the predetermined probe geometry and the predetermined
assumed sample fluid density.
2. The method of claim 1, further comprising comparing the calculated
volume to a predetermined reference volume.
3. The method of claim 2, further comprising providing a signal if the
calculated volume differs from the predetermined reference volume by a
predetermined amount.
4. The method of claim 1, wherein determining the time of an initial rise
further comprises detecting a rate of change of pressure of at least a
predetermined value for a predetermined period of time.
5. The method of claim 4, wherein determining the time of an initial decay
further comprises detecting a rate of change of pressure of at least a
predetermined value for a predetermined period of time.
6. The method of claim 1, further comprising:
calculating an elapsed time between the time of the initial rise and the
time of the initial decay; and
comparing the elapsed time with a predetermined time reference value.
7. The method of claim 5, further comprising providing a signal if the
calculated elapsed time differs from the predetermined time reference
value by a predetermined amount.
8. The method of claim 1, further comprising normalizing the pressure
measured within the sample probe to a reference value prior to aspiration
of the fluid.
9. The method of claim 8, wherein the reference value is 0 psi.
10. The method of claim 1 wherein said step of determining a time of an
initial rise in vacuum of the pressure profile comprises taking a first
derivative of the pressure profile.
11. The method of claim 1 wherein said step of determining a time of an
initial decay in vacuum of the pressure profile comprises taking a first
derivative of the pressure profile.
Description
STATEMENT OF FEDERALLY SPONSORED RESEARCH
None
RELATED APPLICATIONS
Not Applicable
BACKGROUND OF THE INVENTION
Automated analyzers are used in clinical laboratories to measure various
chemical constituents of body fluids, such as whole blood, blood serum,
blood plasma, cerebral spinal fluid, urine, and the like obtained from
patients. Automated analyzers reduce the number of trained technicians
required to perform the analyses in a clinical laboratory, improve the
accuracy of the testing, and reduce the cost per test.
Typically, an automated analyzer includes an automated fluid moving system
which aspirates a sample of body fluid from a patient's specimen container
and dispenses the sample into a reaction cuvette. The fluid moving system
typically includes a pipette or sample probe on a robotically controlled
arm to perform the aspiration and dispensing functions.
Chemical reagents, which are specific to the test being performed, are
disposed into the sample-containing cuvette, thereby mixing the sample
with the chemical reagents. By examining the reaction products resulting
from the mixing of the sample and reagents, the automated analyzer
determines the concentration of the specific chemical constituent being
tested. Upon completion of the test, the automated analyzer typically
prints the results of the test, including a sample identifier, a numerical
result of the test, and a range of values for the chemical constituent as
measured by the test.
During an aspiration operation, the robotic arm, under the command of a
system controller, positions the sample probe above a specimen container
and moves the probe into the container until the probe reaches the fluid
in the container. A syringe type pump is activated to draw sample fluid
from the specimen container into the probe. To ensure that accurate
results are obtained in the tests, a consistent known volume of the sample
must be accurately aspirated and delivered to the reaction cuvette. Under
ideal conditions, motorized syringes can deliver the volume at the needed
accuracy. However, conditions are not always ideal, so a method of
verifying sample volume is needed.
Prior art methods have focused on detecting non-ideal conditions. In one
method, pressure is measured after each increment of aspiration. A
pressure value outside a predetermined pressure range signals a
heterogeneity in the sample. Khalil, Omar S. et al., "Abbott Prism: A
Multichannel Heterogeneous Chemiluminescence Immunoassay Analyzer," Clin.
Chem., 37/9, 1540-47 (1991). European Patent Application No. 341,438
describes a system in which pressure is also monitored during aspiration.
Bubbles, a clot, or a pressure leak are shown on a display screen as one
or more spikes. European Patent Application No. 215,534 describes a system
in which pressure after a suction operation is measured and compared to an
expected normal value.
SUMMARY OF THE INVENTION
The present invention provides a method of verifying sample volume by
quantifying the fluid volume aspirated and of verifying sample uniformity
by detecting non-ideal conditions such as the presence of foam or clots in
the sample.
A pressure sensor is used to measure the vacuum needed to hold up the
column of aspirated fluid in the probe tip. This value is measured by
determining the pressure difference between the start and the end of the
aspiration. The pressures at the start and at the end of the aspiration
are determined by looking for a significant rate of change in the
pressure, upward at the start and downward at the end. By knowing the
geometry of the probe tip, the pressure difference can be converted to a
sample weight. The sample weight can be converted to a sample volume by
assuming a sample density. The calculated volume can then be compared to
the expected volume for a given probe geometry. Non-ideal conditions, such
as foam on the surface of the fluid or a clot in the fluid, result in an
apparent sample volume much lighter, in the case of foam, or much greater,
in the case of a clot, than anticipated. Also, in the case of foam in the
sample, the pressure decay begins much earlier than expected in a normal
sample; in the case of a clot in the sample, the pressure decay begins
much later than expected in a normal sample. Thus, a comparison of the
measured elapsed time of the aspiration to the expected elapsed time
provides another indication of sample non-uniformity.
The present method allows for a direct quantification of the amount of
fluid aspirated. By making use of the rates of change of the pressure
measurements, the present method is less susceptible to normal variances
in fluid properties. Additionally, the present method makes use of a
combined approach to verify that a correct amount of fluid is aspirated.
BRIEF DESCRIPTION OF THE DRAWINGS
The invention will be better understood by referring to the detailed
description taken in conjunction with the following drawings, in which:
FIG. 1 is a schematic diagram of an aspirating and dispensing system
according to the present invention;
FIG. 2 is a block diagram of a pressure sensor system;
FIG. 3 is a graph of pressure (vacuum) versus time illustrating an
aspiration of a normal sample (dashed line) and an aspiration of a foamy
sample (solid line); and
FIG. 4 is a graph of pressure (vacuum) versus time illustrating an
aspiration of a normal sample (dashed line) and an aspiration of a clotted
sample (solid line).
DETAILED DESCRIPTION OF THE INVENTION
Referring to FIG. 1, aspirating and dispensing apparatus 10 includes an air
source, such as an air pump 12 coupled through an air vent 14 to an
accumulator 16. The air source should be able to provide a constant air
flow at a predetermined rate and pressure. The air pump may be a small
rotary type pump. The accumulator typically comprises a coil of long
tubing wrapped around a cylinder and serves to dampen the pulsations from
the pump. In this manner, the output from the accumulator is a consistent
flow of air with few or no pulses.
A bleed valve 18 is located downstream of the accumulator. Downstream of
the bleed valve is a pump valve 20. The pump valve is a three way valve
including a normally open port 22 to downstream and a normally closed port
24 to a vent. A tee connector 26 is coupled to the downstream port of the
pump valve. One branch of the tee connector is coupled to a motorized
syringe-type pump or dilutor 28 and the other branch of the tee connector
is coupled to a sample probe 30.
A flow-through pressure sensor or transducer 32 is provided between the tee
connector 26 and the sample probe 30. A suitable pressure sensor is
manufactured by the Micro Switch Division of Honeywell Corporation
identified as a 26PC Series pressure transducer. The sensitivity of the
sensor corresponds to about 16 mV/psi of pressure difference. Other
pressure sensors having suitable fluid and electrical characteristics can
be used. Preferably, the pressure sensor is located close to the sample
probe to improve the signal to noise ratio of the pressure measurements.
The sample probe is mounted on a robot arm 34. Typically, the probe
includes a probe body 36 and a probe tip 38. The tip is usually disposable
and removably coupled to the probe body. A supply of tips is stored where
they are accessible by the probe upon movement by the robot arm. However,
in some applications, a non-disposable tip permanently secured to the
probe body may be used.
A system controller 40 is provided in communication with the air pump 12,
bleed valve 18, pump valve 20, dilutor 28, and robot arm 34 to control
operation of the system and with the pressure sensor 32 to receive
pressure measurements. An aspirating and dispensing system of the present
type is also described in Application No. 08/501,806 filed on Jul. 13,
1995, now U.S. Pat. No. 5,750,881, entitled METHOD AND APPARATUS FOR
ASPIRATING AND DISPENSING SAMPLE FLUIDS, assigned to the assignee of this
application. The disclosure of Application No. 08/501,806 is incorporated
by reference herein.
In operation during an aspiration, the air pump 12 is turned on, forcing
air through the probe 30. The robot arm 34 positions the probe, with a
probe tip attached, above a specimen container 42 and moves the probe into
the container until the probe reaches the fluid therein. When the probe
touches the fluid, the pressure sensor detects a rise in pressure. The air
pump is turned off, and the bleed valve 18 is opened to depressurize the
system. The pump valve 20 is then closed to isolate the pump 12 and the
accumulator 16 from the probe 30 and the dilutor 28, and the dilutor is
operated to draw a volume of the sample into the probe.
Referring to FIG. 2, the pressure sensor 32 includes a pair of fluid ports
52, 54 and a pair of electrical signal terminals 56, 58 coupled to an
amplifier circuit 60. The air pressure measured at the sensor 32 provides
a corresponding differential voltage signal to the amplifier circuit 60,
which provides a single amplified output signal on a terminal 62. The
amplifier circuit is preferably coupled to a pressure normalization
circuit 64. The pressure normalization circuit, using sample and hold
circuitry as is known in the art, normalizes the amplified pressure signal
to a reference level, typically 0 volts, upon a signal from the
controller. A relative pressure measurement is required when the system is
to measure the amount of vacuum needed to hold up the column of fluid in
the probe.
In determining the amount of vacuum needed to hold up the column of fluid,
the pressure of the aspiration is measured over time. The pressure profile
of a normal sample is illustrated in FIGS. 3 and 4, shown by a dashed line
and the notation "Aspiration of Normal Sample (1)". Once the aspiration
begins, an initial rise in vacuum from a reference level occurs. The
pressure rise begins to level off, and after a period of time, the vacuum
decays, indicated by the notation "Initial decay (1)" in FIGS. 2 and 3.
The pressure comes to rest at a final level, indicated by the notation
"Final Level (1)." This pressure is the amount of vacuum required to hold
up the fluid in the probe.
From the measured pressure profile, four key reference values are
determined:
1) T.sub.rise, the time at which the initial rise in pressure signal
occurs;
2) P.sub.init, the vacuum pressure just prior to the initial vacuum rise,
preferably normalized to 0 psi;
3) T.sub.decay, the time at which the initial decay in pressure signal
occurs; and
4) P.sub.final, the vacuum pressure at a specified time after the initial
decay.
The two time-based reference values, T.sub.rise and T.sub.decay, are
preferably determined numerically by examining the pressure sensor for the
first significant upward and downward pressure changes respectively. The
pressure sensor is sampled at predetermined time intervals, such as, for
example, every 2 msec. The pressure changes are triggered, for example, by
a rate of change of about 1 psi/sec occurring over a 3-4 msec time period.
The starting time of each change is recorded, and the elapsed time for the
aspiration is calculated as the difference between these two times.
For example, in a normal aspiration of about 100 .mu.l, P.sub.final may be
about 0.07 psig (where P.sub.init has been normalized to 0 psi). The
elapsed time may be about 500 msec. The average pressure change over the
aspiration is about 0.14 psi/sec. T.sub.rise and T.sub.final are therefore
triggered by pressure changes of about 10 times the expected average
pressure change over the aspiration.
The pressure reading P.sub.init is taken just prior to the starting time of
the initial rise. The pressure reading P.sub.final is taken at a specified
time after the initial decay. Typically, this reading is taken 300 msec
after the initial delay to allow for stabilization of the system. To
better characterize the pressure readings, it is preferable to determine a
time averaged value for each reading. The time averaged readings are
determined numerically by averaging the pressure readings over a
predetermined time interval, such as 50 to 100 msec.
The difference between the pressure reading P.sub.init and the pressure
reading P.sub.final is recorded as the pressure change for the aspiration.
The pressure change for the aspiration is used to determine the volume of
fluid in the sample tip. This can be done if both the density of the fluid
and the geometry of the sample tip are known. The pressure difference,
P.sub.final -P.sub.init, can be converted into a fluid column height if
the density is known. The fluid volume can be calculated from the fluid
column height based on the geometry of the sample tip. Densities for
various samples, such as blood serum, are generally known. For samples
which may typically have a known range of densities, a mid point within
the known range may be chosen for the calculation. Non-ideal conditions,
such as foam on the sample surface or clots in the sample result in
calculated volumes out of the anticipated values. Foam results in a sample
volume less than expected. A clot results in a sample volume greater than
expected.
FIG. 3 also illustrates a pressure profile of a foamy sample, shown by the
solid line and the notation "Aspiration of Foamy Sample (2)," which
results in a low calculated aspiration volume. In this case, the initial
decay, indicated by "Initial Decay (2)," occurs shortly after the initial
rise. The elapsed time of the aspiration is thus less than normal. Also,
the final pressure reading, indicated by "Final Level (2)," is less than
the final pressure reading of a normal sample.
FIG. 4 also illustrates a pressure profile of a clotted sample, shown by
the solid line and the notation "Aspiration of Clotted Sample (3)," which
results in a high calculated aspiration volume. In this case, the pressure
reading contines to rise to a value greater than expected from a normal
sample before decaying, indicated by "Initial Decay (3)." The final
pressure reading, indicated by "Final Level (3)," is greater than the
final pressure reading of a normal sample.
Upon detection of a volume or an elapsed time different than that expected
for a particular sample, the system provides a signal, which may be a
visible or audible alarm. The calculation of sample volume and elapsed
time may be implemented in any suitable manner, such as by a programmed
microprocessor or by circuitry.
Having shown the preferred embodiment, those skilled in the art will
realize many variations are possible which will still be within the scope
and spirit of the claimed invention. Therefore, it is the intention to
limit the invention only as indicated by the scope of the claims.
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